Tolypocladium sinense Mycelium Polysaccharide Alleviates Obesity, Lipid Metabolism Disorder, and Inflammation Caused by High Fat Diet via Improving Intestinal Barrier and Modulating Gut Microbiota.

SCOPE: Tolypocladium sinense is a fungus isolated from Cordyceps. Cordyceps has some medicinal value and is also a daily health care product. This study explores the preventive effects of T. sinense mycelium polysaccharide (TSMP) on high-fat diet-induced obesity and chronic inflammation in mice. METHODS AND RESULTS: Here, the study establishes an obese mouse model induced by high-fat diet. In this study, the mice are administered TSMP daily basis to evaluate its effect on alleviating obesity. The results show that TSMP can significantly inhibit obesity and alleviate dyslipidemia by regulating the expression of lipid metabolism-related genes such as liver kinase B1 (LKB1), phosphorylated AMP-activated protein kinase (pAMPK), peroxisome proliferator activated receptor α (PPARα), fatty acid synthase (FAS), and hydroxymethylglutaryl-CoA reductase (HMGCR) in the liver. TSMP can increase the protein expression of zona occludens-1 (ZO-1), Occludin, and Claudin-1 in the colon, improve the intestinal barrier dysfunction, and reduce the level of serum LPS, thereby reducing the inflammatory response. 16S rDNA sequencing shows that TSMP alters the intestinal microbiota by increasing the relative abundance of Akkermansia, Lactobacillus, and Prevotellaceae_NK3B31_group, while decreasing the relative abundance of Faecalibaculum. CONCLUSION: The findings show that TSMP can inhibit obesity and alleviates obesity-related lipid metabolism disorders, inflammatory responses, and oxidative stress by modulating the gut microbiota and improving intestinal barrier.

Attenuated Salmonella carrying siRNA-PD-L1 and radiation combinatorial therapy induces tumor regression on HCC through T cell-mediated immuno-enhancement.

Hepatocellular carcinoma (HCC), the most prevalent type of aggressive liver cancer, accounts for the majority of liver cancer diagnoses and fatalities. Despite recent advancements in HCC treatment, it remains one of the deadliest cancers. Radiation therapy (RT) is among the locoregional therapy modalities employed to treat unresectable or medically inoperable HCC. However, radioresistance poses a significant challenge. It has been demonstrated that RT induced the upregulation of programmed death ligand 1 (PD-L1) on tumor cells, which may affect response to PD-1-based immunotherapy, providing a rationale for combining PD-1/PD-L1 inhibitors with radiation. Here, we utilized attenuated Salmonella as a carrier to explore whether attenuated Salmonella carrying siRNA-PD-L1 could effectively enhance the antitumor effect of radiotherapy on HCC-bearing mice. Our results showed that a combination of siRNA-PD-L1 and radiotherapy had a synergistic antitumor effect by inhibiting the expression of PD-L1 induced by radiation therapy. Mechanistic insights indicated that the combination treatment significantly suppressed tumor cell proliferation, promoted cell apoptosis, and stimulated immune cell infiltration and activation in tumor tissues. Additionally, the combination treatment increased the ratios of CD4+ T, CD8+ T, and NK cells from the spleen in tumor-bearing mice. This study presents a novel therapeutic strategy for HCC treatment, especially for patients with RT resistance.

Physalis alkekengi L. Calyx Extract Alleviates Glycolipid Metabolic Disturbance and Inflammation by Modulating Gut Microbiota, Fecal Metabolites, and Glycolipid Metabolism Gene Expression in Obese Mice.

Physalis alkekengi L. calyx (PC) extract can relieve insulin resistance and has glycemic and anti-inflammatory effects; however, the potential mechanisms related to gut microbiota and metabolites remain elusive. This study aimed to understand how PC regulates gut microbiota and metabolites to exert anti-obesogenic effects and relieve insulin resistance. In this study, a high-fat high-fructose (HFHF)-diet-induced obesity C57BL/6J male mice model with glycolipid metabolism dysfunction was established, which was supplemented with the aqueous extract of PC daily for 10 weeks. The results showed that the PC supplementation could effectively cure the abnormal lipid metabolism and maintain glucose metabolism homeostasis by regulating the expression of adipose metabolic genes and glucose metabolism genes in the liver, thereby effectively alleviating the inflammatory response. PC treatment also increased the contents of fecal short-chain fatty acids (SCFAs), especially butyric acid. PC extract could restore the HFHF-disrupted diversity of gut microbiota by significantly increasing the relative abundance of Lactobacillus and decreasing those of Romboutsia, Candidatus_Saccharimonas, and Clostridium_sensu_stricto_1. The negative effects of the HFHF diet were ameliorated by PC by regulating multiple metabolic pathways, such as lipid metabolism (linoleic acid metabolism, alpha-linolenic acid metabolism, and sphingolipid metabolism) and amino acid metabolism (histidine and tryptophan metabolism). Correlation analysis showed that among the obesity parameters, gut microbiota and metabolites are directly and closely related. To sum up, this study suggested that PC treatment exhibited therapeutic effects by regulating the gut microbiota, fecal metabolites, and gene expression in the liver to improve glucose metabolism, modulate adiposity, and reduce inflammation.

Ginsenoside Rg3 Protects Mouse Islet ß-Cells Injured by High Glucose.

To investigate the effect of Ginsenoside Rg3 on insulin secretion in mouse MIN6 cells and the possible mechanism. The cultured mouse pancreatic islet MIN6 cells were divided into control group (NC), Rg3 group (Rg3, 50 µg/L), high glucose group (HG, 33 mmol/L), High glucose and Rg3 group (HG + Rg3), after 48 h of continuous culture, CCK-8 was used to detect cell viability; mouse insulin enzyme-linked immunoassay kit to detect insulin release; ATP content detection kit to detect ATP; DCFH-DA to detect intracellular reactive oxygen species (ROS) levels; total glutathione (T-GSH)/oxidized glutathione (GSSG) assay kit to detect the ratio of GSH/GSSG; Using the mitochondrial membrane channel pore (MPTP) fluorescence detection kit in MIN6 cells and collect the intensity of green fluorescence; Western blot to detect the expression of antioxidant proteins Glutathione reductase (GR). The results showed that compared with the NC group, the cell viability of the HG was decreased (P < 0.05), insulin release decreased (P < 0.001), ATP content decreased significantly (P < 0.001), and ROS content increased (P < 0.01), the GSH/GSSH ratio of pancreatic islet cells decreased (P < 0.05),the green fluorescence intensity decreased (P < 0.001), indicating that the permeability of mitochondria increased and the content of antioxidant protein in the cells decreased (P < 0.05). Compared with the HG group, the cell viability of the HG + Rg3 group was significantly increased (P < 0.05), the amount of insulin released was significantly increased (P < 0.001), ATP content was significantly increased (P < 0.01), and the ROS content was significantly decreased (P < 0.01), GSH/GSSH ratio increased significantly (P < 0.05), the green fluorescence intensity was increased (P < 0.001), indicating that the permeability of mitochondria decreased and antioxidant protein GR content increased significantly (P < 0.05). Taken together, our results suggest that Rg3 has an antioxidant protective effect on mouse pancreatic islet cells damaged by high glucose and maintains pancreatic islet cell function and promotes insulin secretion.

Antimicrobial Application of Chitosan Derivatives and their Nanocomposites.

Chitosan is derived from chitin polysaccharide, the main component of crustacean shells. Chitosan is a biocompatible, nontoxic, and biodegradable polymer soluble in acidic solutions. It is widely used in the medical and pharmaceutical fields. Antimicrobial activities of chitosan against different bacterial, fungal, and viral pathogens have been considered one of its attractive properties, making chitosan valuable for biological applications, including textile, food, tissue engineering, agriculture, and environmental protection. Additionally, chitosan has beneficial effects on livestock, poultry, fish, and crustaceans, which can enhance immunity, improve feed conversion, and promote growth. However, the water solubility of chitosan influences antimicrobial capabilities, limiting its application. In the present work, we reviewed the preparation, factors affecting antimicrobial activity, morphological structure, antimicrobial mechanism, and application of chitosan derivatives, and the problems and prospects were pointed out. Collectively, this review provided an update on the application of chitosan derivatives and their potential for further advanced applications in the antimicrobial field.

Chitosan-Based Nanomaterial as Immune Adjuvant and Delivery Carrier for Vaccines.

With the support of modern biotechnology, vaccine technology continues to iterate. The safety and efficacy of vaccines are some of the most important areas of development in the field. As a natural substance, chitosan is widely used in numerous fields-such as immune stimulation, drug delivery, wound healing, and antibacterial procedures-due to its good biocompatibility, low toxicity, biodegradability, and adhesion. Chitosan-based nanoparticles (NPs) have attracted extensive attention with respect to vaccine adjuvants and delivery systems due to their excellent properties, which can effectively enhance immune responses. Here, we list the classifications and mechanisms of action of vaccine adjuvants. At the same time, the preparation methods of chitosan, its NPs, and their mechanism of action in the delivery system are introduced. The extensive applications of chitosan and its NPs in protein vaccines and nucleic acid vaccines are also introduced. This paper reviewed the latest research progress of chitosan-based NPs in vaccine adjuvant and drug delivery systems.

Dietary supplementation with Tolypocladium sinense mycelium prevents dyslipidemia inflammation in high fat diet mice by modulation of gut microbiota in mice.

Obesity is a risk factor for many serious health problems, associated with inflammation, hyperlipidemia, and gut dysbiosis. Prevention of obesity is especially important for human health. Tolypocladium sinense is one of the fungi isolated from Chinese caterpillar fungus, which is a traditional Chinese medicine with putative gut microbiota modulation effects. Here, we established a high-fat diet (HFD)-induced hyperlipidemia mice model, which was supplemented with lyophilized T. sinense mycelium (TSP) daily to evaluate its anti-obesity effects. The results indicated that TSP supplementation can effectively alleviate the inflammatory response and oxidative stress levels caused by obesity. TSP significantly prevented obesity and suppressed dyslipidemia by regulating the expression of lipid metabolism genes in the liver. TSP is also effective in preventing the HFD-induced decline in short-chain fatty acid (SCFA) content. Gut microbiota profiling showed that TSP supplementation reversed HFD diet-induced bacterial abundance and also altered the metabolic pathways of functional microorganisms, as revealed by KEGG analysis. It is noteworthy that, correlation analysis reveals the up-regulated gut microbiota (Lactobacillus and Prevotella_9) are closely correlated with lipid metabolism parameters, gene expression of liver lipid metabolism and inflammatory. Additionally, the role of TSP in the regulation of lipid metabolism was reconfirmed by fecal microbiota transplantation. To sum up, our results provide the evidence that TSP may be used as prebiotic agents to prevent obesity by altering the gut microbiota, alleviating the inflammatory response and regulating gene expression of liver lipid metabolism.

Indole-3-Carbinol Stabilizes p53 to Induce miR-34a, Which Targets LDHA to Block Aerobic Glycolysis in Liver Cancer Cells.

Certain cancer cells prefer aerobic glycolysis rather than oxidative phosphorylation for energy supply. Lactate dehydrogenase A (LDHA) catalyzes the reduction of pyruvate to lactate and regains NAD+ so that glycolysis is continued. As a pivotal enzyme to promote smooth glycolysis, LDHA plays an important role in carcinogenesis. Indole-3-carbinol (I3C) has displayed antitumor activity, but the exact mechanism remains to be identified. In this study, we treated liver cancer cells with I3C, performed colony formation and cell migration, measured the expression of glycolysis-related proteins, and predicted and validated LDHA-targeting miRNA from the databases. In addition, the mRNA and protein levels of p53, glycolysis-related genes and miRNAs that regulate glycolysis were detected after I3C and siRNA-p53 treatment alone or in combination. Next, the expression and colocalization of p53 and MDM2 in liver cancer cells were evaluated after I3C treatment, and the effect of I3C on p53 protein stability was examined. The results showed that I3C inhibited cell proliferation, migration, and the expression levels of glycolysis-related gene LDHAs. MiR-34a was predicted to target LDHA, and I3C downregulated its expression. Furthermore, the combined I3C and siRNA-p53 treatment demonstrated that I3C regulated the expression of LDHA via miR-34a in a p53-dependent manner. Finally, I3C inhibited MDM2 expression and its colocalization with p53 and stabilized p53 expression. In summary, I3C inhibited the degradation of p53 by MDM2 in liver cancer cells; stable p53 induced miR-34a, which targeted LDHA, a key enzyme for aerobic glycolysis, suggesting cancer metabolism is an important target for I3C in liver cancer cells.

Immune enhancement of N-2-Hydroxypropyl trimethyl ammonium chloride chitosan/carboxymethyl chitosan nanoparticles vaccine.

The immunogenicity and toxicity of N-2-Hydroxypropyl trimethyl ammonium chloride chitosan/N, O-carboxymethyl chitosan nanoparticles (N-2-HACC/CMCS NPs) as a universal vaccine adjuvant/delivery system remains unclear. The present study indicated that the positively charged N-2-HACC/CMCS NPs showed a regular spherical morphology, with a particle size of 219 ± 13.72 nm, zeta potential of 37.28 ± 4.58 mV, had hemocompatibility and biodegradation. Acute toxicity, repeated dose toxicity, abnormal toxicity, muscle stimulation, whole body allergic reaction evaluation in vitro, and cytotoxicity in vivo confirmed N-2-HACC/CMCS NPs is safe and non-toxic. N-2-HACC/OVA/CMCS NPs were prepared to evaluate the immunogenicity, which showed a particle size of 248.1 ± 15.53 nm, zeta potential of 17.24 ± 1.28 mV, encapsulation efficiency of 92.43 ± 0.96 %, and loading capacity of 42.97 ± 0.07 %. Oral or intramuscular route with the N-2-HACC/OVA/CMCS NPs in mice not only induced higher IgG, IgG1, IgG2a, and sIgA antibody titers, but also significantly produced higher levels of IL-6, IL-4, IFN-γ, and TNF-α, demonstrating that the N-2-HACC/OVA/CMCS NPs enhance humoral, cellular, and mucosal immune responses. Our results not only support the N-2-HACC/CMCS NPs to be a safe and potential universal nano adjuvant/delivery system in vaccine development, especially mucosal vaccines, but also rich the database knowledge of adjuvant/delivery systems, and provide new direction to introduce more licensed adjuvants.

Synchronous electrochemical detection of dopamine and uric acid by a PMo12@MIL-100(Fe)@PVP nanocomposite.

In this work, a noble-metal-free composite electrode was prepared based on PMo12O403- (PMo12), C9H5FeO7 (MIL-100(Fe), a Fe-based metal organic framework) and polyvinylpyrrolidone (PVP), and served as a high performance electrochemical sensor for synchronous detection of dopamine (DA) and uric acid (UA). The PMo12@MIL-100(Fe)@PVP composite electrode was fabricated by a in-situ hydrothermal method. Thanks to the synergistic effect of three active components (PMo12, MIL-100 and PVP), the electrode possesses large specific surface area and high electrical conductivity and therefore it shows high electrocatalytic oxidation performance of DA and UA with a spacing of 0.146 V between the two peak positions. These benefits of the electrode enable its electrochemical sensor to synchronously detect of DA and UA. Namely, the linear ranges can achieve 1-247 µM for DA and 5-406 µM for UA. Meanwhile, the detection limits are 0.586 µM for DA and 0.372 µM for UA. Moreover, the sensor can be applied to simultaneous determination of UA and DA in human serums with satisfactory recovery values.

3D-Printed Flexible Phase-Change Nonwoven Fabrics toward Multifunctional Clothing.

Functional phase-change fabrics hold great promise as wearable clothing. However, how to enable a phase-change fabric with the combined features of excellent structural flexibility and robustness, integrated multifunctionality, superior stability, and durability, as well as facile and scalable manufacturing, still remains a significant challenge. Herein, we demonstrated a scalable and controllable three-dimensional (3D) printing strategy for manufacturing flexible, thin, and robust phase-change nonwoven fabric (PCNF), with abundant and regular breathable pores as well as uniform and tight embedment of highly interconnected single-walled carbon nanotubes (SWNTs) into hydrophobic filaments built by intertwining solid-solid phase-change polymer chains together. The remarkable architectural features enabled an integral whole of the fabric, ready air exchange, superior water impermeability, highly efficient heat harvesting and storage, and effective absorption and reflection of electromagnetic waves, thereby delivering an exceptional combined function of breathability, waterproofness, thermal regulation, and radiation resistance, and meanwhile featuring superior thermal stability and outstanding resistance to stretching/folding fatigue even at cycles up to 2000. This work sheds light on effective strategies for manufacturing wearable phase-change fabrics with multifunctionality and high stability in a scalable manner toward future uses.

Alterations and correlations of gut microbiota, fecal, and serum metabolome characteristics in a rat model of alcohol use disorder.

Background: Growing evidence suggests the gut microbiota and metabolites in serum or fecal may play a key role in the process of alcohol use disorder (AUD). However, the correlations of gut microbiota and metabolites in both feces and serum in AUD subjects are not well understood. Methods: We established a rat model of AUD by a chronic intermittent ethanol voluntary drinking procedure, then the AUD syndromes, the gut microbiota, metabolomic profiling in feces and serum of the rats were examined, and correlations between gut microbiota and metabolites were analyzed. Results: Ethanol intake preference increased and maintained at a high level in experimental rats. Anxiety-like behaviors was observed by open field test and elevated plus maze test after ethanol withdraw, indicating that the AUD rat model was successfully developed. The full length 16S rRNA gene sequencing showed AUD significantly changed the ß-diversity of gut microbial communities, and significantly decreased the microbial diversity but did not distinctly impact the microbial richness. Microbiota composition significantly changed in AUD rats, such as the abundance of Romboutsia and Turicibacter were significantly increased, whereas uncultured_bacterium_o_Mollicutes_RF39 was decreased. In addition, the untargeted metabolome analysis revealed that many metabolites in both feces and serum were altered in the AUD rats, especially involved in sphingolipid metabolism and glycerophospholipid metabolism pathways. Finally, multiple correlations among AUD behavior, gut microbiota and co-changed metabolites were identified, and the metabolites were directly correlated with the gut microbiota and alcohol preference. Conclusion: The altered metabolites in feces and serum are important links between the gut microbiota dysbiosis and alcohol preference in AUD rats, and the altered gut microbiota and metabolites can be potentially new targets for treating AUD.

{BiW8 O30 } Exerts Antitumor Effect by Triggering Pyroptosis and Upregulating Reactive Oxygen Species.

We successfully synthesized {BiW8 }, a 10-nuclear heteroatom cluster modified {BiW8 O30 }. At 24 h post-incubation, the IC50 values of {BiW8 } against HUVEC, MG63, RD, Hep3B, HepG2, and MCF7 cells were 895.8, 127.3, 344.3, 455.0, 781.3, and 206.3 µM, respectively. The IC50 value of {BiW8 } on the MG63 cells was more than 2-fold lower than that of the other raw materials. Through morphological and functional features, we demonstrated pyroptosis as a newly identified mechanism of cell death induced by {BiW8 }. {BiW8 } increased 2-fold reactive oxygen species (ROS) levels in MG63 cells at 24 h post-incubation. Compared with 0 h, the glutathione (GSH) content decreased by 59, 65, 75, 94, and 97 % at 6, 12, 24, 36 and 48 h post-incubation, respectively. Furthermore, multiple antitumor mechanisms of {BiW8 } were identified via transcriptome analysis and chemical simulation, including activation of pyroptosis, suppression of GSH generation, depletion of GSH, and inhibition of DNA repair.

Sieve-Like CNT Film Coupled with TiO2 Nanowire for High-Performance Continuous-Flow Photodegradation of Rhodamine B under Visible Light Irradiation.

Continuous-flow photoreactors hold great promise for the highly efficient photodegradation of pollutants due to their continuity and sustainability. However, how to enable a continuous-flow photoreactor with the combined features of high photodegradation efficiency and durability as well as broad-wavelength light absorption and large-scale processing remains a significant challenge. Herein, we demonstrate a facile and effective strategy to construct a sieve-like carbon nanotube (CNT)/TiO2 nanowire film (SCTF) with superior flexibility (180° bending), high tensile strength (75-82 MPa), good surface wettability, essential light penetration and convenient visible light absorption. Significantly, the unique architecture, featuring abundant, well-ordered and uniform mesopores with ca. 70 µm in diameter, as well as a homogenous distribution of TiO2 nanowires with an average diameter of ca. 500 nm, could act as a "waterway" for efficient solution infiltration through the SCTF, thereby, enabling the photocatalytic degradation of polluted water in a continuous-flow mode. The optimized SCTF-2.5 displayed favorable photocatalytic behavior with 96% degradation of rhodamine B (RhB) within 80 min and a rate constant of 0.0394 min-1. The continuous-flow photodegradation device made using SCTF-2.5 featured exceptional photocatalytic behavior for the continuous degradation of RhB under simulated solar irradiation with a high degradation ratio (99.6%) and long-term stability (99.2% retention after working continuously for 72 h). This work sheds light on new strategies for designing and fabricating high-performance continuous-flow photoreactors toward future uses.

Meta-analysis: Interleukin 6 gene -174G/C polymorphism associated with type 2 diabetes mellitus and interleukin 6 changes.

The gene coding interleukin 6 (IL-6) is a promising candidate in predisposition to type 2 diabetes mellitus (T2DM). This study aimed to meta-analytically examine the association of IL-6 gene -174G/C polymorphism with T2DM and circulating IL-6 changes across -174G/C genotypes. Odds ratio (OR) and standard mean difference (SMD) with 95% confidence interval (CI) were calculated. Twenty-five articles were meta-analysed, with 20 articles for T2DM risk and 9 articles for circulating IL-6 changes. Overall, there was no detectable significance for the association between -174G/C polymorphism and T2DM, and this association was relatively obvious under dominant model (OR: 0.82, 95% CI: 0.56-1.21). Improved heterogeneity was seen in some subgroups, with statistical significance found in studies involving subjects of mixed races (OR: 0.63, 95% CI: 0.46-0.86). Begg's and filled funnel plots, along with Egger's tests revealed week evidence of publication bias. In genotype-phenotype analyses, carriers of -174CC and -174CG genotypes separately had 0.10 and 0.03 lower concentrations (pg/mL) of circulating IL-6 than -174GG carriers. Albeit no detectable significance for the association of -174G/C with T2DM, our findings provided suggestive evidence on a dose-dependent relation between -174G/C mutant alleles and circulating IL-6 concentrations, indicating possible implication of this polymorphism in the pathogenesis of T2DM.

Susceptibility of six polymorphisms in the receptor for advanced glycation end products to type 2 diabetes: a systematic review and meta-analysis.

We did a systematic review and meta-analysis, aiming to examine the association of available polymorphisms in the receptor for advanced glycation end products (AGER) gene with the risk of type 2 diabetes. Literature search, eligibility assessment, and data extraction were independently performed by two authors. Risk was expressed as by odds ratio (OR) and 95% confidence interval (CI) under the random-effects model. A total of 26 publications, involving 29 independent studies (8,318 patients with type 2 diabetes and 5,589 healthy or orthoglycemic controls) were included in this meta-analysis. Six polymorphisms in AGER gene, rs2070600, rs1800624, rs1800625, rs184003, rs3134940, and rs55640627, were eligible for inclusion. Overall analyses indicated that the mutations of rs1800624 (-374A) and rs55640627 (2245A) were associated with a significantly increased risk of type 2 diabetes (OR = 1.17 and 1.55, 95% CI: 1.00 to 1.38 and 1.21 to 1.98, respectively). Subsidiary analyses revealed that the mutation of rs2070600 was associated with 2.13-folded increased risk of type 2 diabetes in Caucasians (95% CI: 1.28 to 3.55), and the mutation of rs1800624 was associated with 1.57-folded increased risk in South Asians (95% CI: 1.09 to 2.25), with no evidence of heterogeneity (I2: 42.5% and 44.5%). There were low probabilities of publication bias for all studied polymorphisms. Taken together, our findings indicate an ethnicity-dependent contribution of AGER gene in the pathogenesis of type 2 diabetes, that is, rs2070600 was a susceptibility locus in Caucasians, yet rs1800624 in South Asians.

Protective Effects of the King Oyster Culinary-Medicinal Mushroom, Pleurotus eryngii (Agaricomycetes), Polysaccharides on ß-Amyloid-Induced Neurotoxicity in PC12 Cells and Aging Rats, In Vitro and In Vivo Studies.

Pleurotus eryngii (PE) contains polysaccharides and vitamins, and has been reported to have antidepression properties. P. eryngii polysaccharides (PEP) are one of the main components. Modulation of ß-amyloid-induced neurotoxicity has emerged as a possible therapeutic approach to ameliorate the onset and progression of Alzheimer's disease (AD). The present study aimed to evaluate the protective effect of PEP on ß-amyloid-induced neurotoxicity in cultured rat pheochromocytoma (PC12) cells and aging rats. After 28 weeks' treatment, exposure of PC12 cells to P. eryngii polysaccharides significantly elevated cell viability, decreased the levels of intracellular calcium, and attenuated the ß-amyloid-mediated cell apoptosis. In aging rats, P. eryngii polysaccharides could decrease the production of APP in the brain by an action that is associated with a lowering of the iNOS, and COX-2 level. Our findings indicated that P. eryngii polysaccharides had potential neuroprotective actions against ß-amyloid-induced neurotoxicity, which might be through modulating calcium channels, or downstream molecules involved in inflammation.

Spatial structure and anti-fatigue of polysaccharide from Inonotus obliquus.

The aim of this study was to evaluate the spatial structure and potential antifatigue activity of polysaccharide fractions which was extracted from Inonotus obliquus. The first polysaccharide fractions of Inonotus obliquus (PIO-1) were obtained after hot-water extraction and purification by DEAE cellulose-52 chromatography. Results of the forced swimming test showed that the doses (50 mg/kg) of PIO-1 could increase the climbing duration and swimming time as well as reduced the immobility time in the PIO treated mice. The fatigue related metabolic parameters showed that PIO-1 decreased the level of blood lactic acid (BLA), urea nitrogen (BUN) and lactic dehydrogenase (LDH). Additionally, PIO-1 significantly decreased the 5-HT concentrations in the mice brain. The results of monosaccharide analysis showed that the molar ratio of mannose, glucose, galactose, xylose and arabinose with the molar ratio of 1.0:1.9:3.5:18.5:5.7. The molecular morphology of the PIO-1 observed under atomic force microscopy (AFM). There were many spherical and heterogeneous clumps existed in the images. Therefore, current study indicated polysaccharide PIO-1 not only has great potential to postpone physical fatigue but also shown potential to improve mental fatigue.

Deletion of miR-126a Promotes Hepatic Aging and Inflammation in a Mouse Model of Cholestasis.

MicroRNAs (miRNAs) act as regulators of aging at the tissue or organism level or as regulators of cellular senescence. Targeted deletion of miR-126 in mice causes partial embryonic lethality, but its biological function in the liver is still largely unknown. Here, we deleted miR-126a, using the CRISPR/Cas9 system in vitro and in vivo. miR-126a was reduced in the aging livers, and disruption of miR-126a in bone mesenchymal stem cells (BMSCs) induced age-associated telomere shortening, DNA damage responses, and proinflammatory cytokines. Moreover, disruption of miR-126a in mice caused hepatocyte senescence, inflammation, and metabolism deficiency. In addition, disruption of miR-126a via BMSC transplantation aggravated the severity of liver defects induced by cholestasis compared with that in the functional miR-126a BMSC group. Mechanistically, we identified versican (VCAN) as a novel direct miR-126a-5p target that induces telomere shortening, BMSC senescence, and nuclear factor κB (NF-κB) pathway activation. This study identified aging-related reduced expression of miR-126a and promotion of its target VCAN as a key mechanism in the regulation of hepatic metabolic function during aging and hepatic damage by inducing NF-κB pathway activation, DNA repair function disorder, and telomere attrition. The findings indicate that miR-126a may be a drug target for the treatment of hepatic failure.

Withaferin A suppresses skin tumor promotion by inhibiting proteasome-dependent isocitrate dehydrogenase 1 degradation.

BACKGROUND: The metabolic enzyme isocitrate dehydrogenase 1 (IDH1) belonging to ß-decarboxylase dehydrogenase family has been identified as a tumor suppressor. Withaferin A (WA), a bioactive compound derived from Withania somnifera, has the anti-tumor activity. Based on the data set that WA inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced IDH1 inactivation and mitochondrial dysfunction, we focused on how WA suppressed the skin carcinogenesis mediated by IDH1. METHODS: The mRNA levels of IDH1 were measured after treated with TPA and/or WA. The expression of IDH1, lactate dehydrogenase (LDH) involved in glycolysis, hypoxia inducible factor-1α (HIF-1α) and its target gene glucose transporter-1 (Glut1) were detected. The activities of proteasome and the mitochondrial complex I related to mitochondrial functions were determined. The enzymatic activities of LDH, proline hydroxylase (PHD) and vascular endothelial growth factor (VEGF) were analyzed. RESULTS: The qPCR data have shown the mRNA levels of IDH1 were no difference with TPA and/or WA treatment. Next, data demonstrated that WA could stabilize IDH1 by inhibiting the ubiquitin-proteasome pathway (UPP). Followed by illuminating the mechanism of IDH1 inhibiting tumorigenesis, the results mirrored that upregulated IDH1 suppressed LDH activity whereas increased mitochondrial complex I activity. Furthermore, via its product α-KG, upregulated IDH1 activated PHD, and inhibited HIF-1α and its downstream signaling pathway. CONCLUSIONS: Our results indicate that WA inhibits tumor promotion partially via stabilizing IDH1, leading to inactivating the HIF-1α signaling.